CLINICAL STUDY: HEART FAILURE
Apoptotic pathway activation from mitochondria and death receptors without caspase-3 cleavage in failing human myocardium
Fragile balance of myocyte survival?
Robert J. Scheubel, MD* ,*,
Babett Bartling, MS*,
Andreas Simm, PhD*,
Rolf-Edgar Silber, MD*,
Kostas Drogaris, MS,
Dorothea Darmer, PhD and
Juergen Holtz, MD
* Clinic for Cardiothoracic Surgery, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
Institute of Pathophysiology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
Manuscript received July 12, 2001;
revised manuscript received October 4, 2001,
accepted November 1, 2001.
* Reprint requests and correspondence: Dr. Robert J. Scheubel, Klinik für Herz- und Thoraxchirurgie, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, D-06097 Halle/Saale, Germany.
robert.scheubel{at}medizin.uni-halle.de
OBJECTIVES: Activation of the caspase cascade through the mitochondrial and/or death receptor pathway was investigated in the failing human myocardium, in which the mode and extent of the cascade activation are unknown.
BACKGROUND: In terminal heart failure, a loss of cardiomyocytes by overload-induced apoptosis is an attractive mechanism, explaining the progressive character of the disease. However, its relevance is unclear, because the specificity of probes for apoptotic deoxyribonucleic acid damage is under debate.
METHODS: Left ventricular specimens from 36 explanted failing and 21 nonfailing donor hearts were used for messenger ribonucleic acid detection by semiquantitative reverse-transcription polymerase chain reaction. From these groups, immunoblot analysis was performed in samples from nine failing and six nonfailing donor hearts.
RESULTS: In terminally failing hearts, there was a significant accumulation of cytochrome c in the cytosol, which was associated with activation of caspase-9 and downregulation of its inhibitor, caspase-9S. Similarly, the death receptor-induced pathway revealed activation of caspase-8, combined with downregulation of its inhibitors, flice-like inhibitory protein-L (FLIPL) and FLIPS. The unspecific caspase inhibitors, XIAP, hIAP-1 and hIAP-2, were also downregulated. However, the terminal effector caspase-3 was not activated, and its substrate gelsolin, acting in its uncleaved form as a feedback inhibitor of caspase-3, was not cleaved.
CONCLUSIONS: In the terminally failing human myocardium, the caspase cascade is partially activated in the presence of a consistent phenotype shift toward enhanced susceptibility to apoptosis. Although the system is still under a fragile control, the partial initiation of the apoptotic program may be of functional relevance also for the surviving cardiomyocytes.
|
Abbreviations and Acronyms
| | TUNEL | | AIF | | apoptosis-inducing factor | | ANP | | atrial natriuretic peptide | | ATP | | adenosine triphosphate | | CAD | | coronary artery disease | | DCM | | dilated cardiomyopathy | | DNA | | deoxyribonucleic acid | | FLIP | | flice-like inhibitory protein | | hIAP | | human inhibitor of apoptosis protein | | HRP | | horseradish peroxidase | | IAP | | inhibitor of apoptosis protein | | IgG | | immunoglobulin G | | mc | | monoclonal | | mRNA | | messenger ribonucleic acid | | RNA | | ribonucleic acid | | RT-PCR | | reverse-transcription polymerase chain reaction | | pc | | polyclonal | | TNF | | tumor necrosis factor | | TUNEL | | terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling | | VAD | | ventricular assist device | | XIAP | | X-linked inhibitor of apoptosis protein |
|
This article has been cited by other articles:
|
|
|
|
 
S. Aharinejad, O. Andrukhova, T. Lucas, A. Zuckermann, G. Wieselthaler, E. Wolner, and M. Grimm
Programmed Cell Death in Idiopathic Dilated Cardiomyopathy is Mediated by Suppression of the Apoptosis Inhibitor Apollon
Ann. Thorac. Surg.,
July 1, 2008;
86(1):
109 - 114.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Bott-Flugel, H.-J. Weig, H. Uhlein, M. Nabauer, K.-L. Laugwitz, and M. Seyfarth
Quantitative analysis of apoptotic markers in human end-stage heart failure
Eur J Heart Fail,
February 1, 2008;
10(2):
129 - 132.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Carlson, D. L. Maass, D. J. White, J. Tan, and J. W. Horton
Antioxidant vitamin therapy alters sepsis-related apoptotic myocardial activity and inflammatory responses
Am J Physiol Heart Circ Physiol,
December 1, 2006;
291(6):
H2779 - H2789.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Moorjani, M. Ahmad, P. Catarino, R. Brittin, D. Trabzuni, F. Al-Mohanna, N. Narula, J. Narula, and S. Westaby
Activation of Apoptotic Caspase Cascade During the Transition to Pressure Overload-Induced Heart Failure
J. Am. Coll. Cardiol.,
October 3, 2006;
48(7):
1451 - 1458.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. Potts, A. E. Vaughn, H. McDonough, C. Patterson, and M. Deshmukh
Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP
J. Cell Biol.,
December 19, 2005;
171(6):
925 - 930.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Abbate, R. Bussani, G. G.L. Biondi-Zoccai, D. Santini, A. Petrolini, F. D. Giorgio, F. Vasaturo, S. Scarpa, A. Severino, G. Liuzzo, et al.
Infarct-related artery occlusion, tissue markers of ischaemia, and increased apoptosis in the peri-infarct viable myocardium
Eur. Heart J.,
October 1, 2005;
26(19):
2039 - 2045.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. P.M. van Empel, A. T.A. Bertrand, L. Hofstra, H. J. Crijns, P. A. Doevendans, and L. J. De Windt
Myocyte apoptosis in heart failure
Cardiovasc Res,
July 1, 2005;
67(1):
21 - 29.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Zhang, J. L. Mott, S.-W. Chang, M. Stevens, P. Mikolajczak, and H. P. Zassenhaus
Mitochondrial DNA mutations activate programmed cell survival in the mouse heart
Am J Physiol Heart Circ Physiol,
May 1, 2005;
288(5):
H2476 - H2483.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. P. Grazette, W. Boecker, T. Matsui, M. Semigran, T. L. Force, R. J. Hajjar, and A. Rosenzweig
Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: Implications for herceptin-induced cardiomyopathy
J. Am. Coll. Cardiol.,
December 7, 2004;
44(11):
2231 - 2238.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D Santini, A Abbate, S Scarpa, F Vasaturo, G G Biondi-Zoccai, R Bussani, F De Giorgio, F Bassan, D Camilot, M P Di Marino, et al.
Surviving acute myocardial infarction: survivin expression in viable cardiomyocytes after infarction
J. Clin. Pathol.,
December 1, 2004;
57(12):
1321 - 1324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Caldarone, E. W. Barner, L. Wang, M. Karimi, C. E. Mascio, J. M. Hammel, J. L. Segar, C. Du, and T. D. Scholz
Apoptosis-related mitochondrial dysfunction in the early postoperative neonatal lamb heart
Ann. Thorac. Surg.,
September 1, 2004;
78(3):
948 - 955.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. M. Scarabelli, E. Pasini, G. Ferrari, M. Ferrari, A. Stephanou, K. Lawrence, P. Townsend, C. Chen-Scarabelli, G. Gitti, L. Saravolatz, et al.
Warm blood cardioplegic arrest induces mitochondrial-mediated cardiomyocyte apoptosis associated with increased urocortin expression in viable cells
J. Thorac. Cardiovasc. Surg.,
September 1, 2004;
128(3):
364 - 371.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mayorga, N. Bahi, M. Ballester, J. X. Comella, and D. Sanchis
Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death
J. Biol. Chem.,
August 13, 2004;
279(33):
34882 - 34889.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Anselmi, A. Abbate, F. Girola, G. Nasso, G. G.L. Biondi-Zoccai, G. Possati, and M. Gaudino
Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: a review of evidence
Eur. J. Cardiothorac. Surg.,
March 1, 2004;
25(3):
304 - 311.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Husse, A. Sopart, and G. Isenberg
Cyclical mechanical stretch-induced apoptosis in myocytes from young rats but necrosis in myocytes from old rats
Am J Physiol Heart Circ Physiol,
October 1, 2003;
285(4):
H1521 - H1527.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R Bussani, A Abbate, G G L Biondi-Zoccai, A Dobrina, A M Leone, D Camilot, M P Di Marino, F Baldi, F Silvestri, L M Biasucci, et al.
Right ventricular dilatation after left ventricular acute myocardial infarction is predictive of extremely high peri-infarctual apoptosis at postmortem examination in humans
J. Clin. Pathol.,
September 1, 2003;
56(9):
672 - 676.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Gonzalez, M. A Fortuno, R. Querejeta, S. Ravassa, B. Lopez, N. Lopez, and J. Diez
Cardiomyocyte apoptosis in hypertensive cardiomyopathy
Cardiovasc Res,
September 1, 2003;
59(3):
549 - 562.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Hammel, C. A. Caldarone, T. L. Van Natta, L. X. Wang, K. F. Welke, W. Li, S. Niles, E. Barner, T. D. Scholz, D. M. Behrendt, et al.
Myocardial apoptosis after cardioplegic arrest in the neonatal lamb
J. Thorac. Cardiovasc. Surg.,
June 1, 2003;
125(6):
1268 - 1275.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Jiang, Y. Huang, S. Hunyor, and C.G. dos Remedios
Cardiomyocyte apoptosis is associated with increased wall stress in chronic failing left ventricle
Eur. Heart J.,
April 2, 2003;
24(8):
742 - 751.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Scheubel, M. Tostlebe, A. Simm, S. Rohrbach, R. Prondzinsky, F. N. Gellerich, R.-E. Silber, and J. Holtz
Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression
J. Am. Coll. Cardiol.,
December 18, 2002;
40(12):
2174 - 2181.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
